Rosuvastatin of the Formula (II) has been disclosed for the first time in European Patent No. 521471. The calcium salt of rosuvastatin is used in the medicine for the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.
The health authorities are setting strict quality criteria towards pharmaceutically active ingredients. Some of these criteria are related to the chemical purity and stability of the pharmaceutically active ingredients. Other official requirement is the manufacture of the medicinal product in satisfactory quality and that the medicinal product shall have appropriate stability. Such criteria are determined by and published in the corresponding articles of pharmacopoeias.
In the case of rosuvastatin of the Formula (II), basic requirements for the active pharmaceutical ingredient intended for the use in medicinal products are high purity, appropriate stability and the possibility of simple formulation.
According to published International Patent Application No. WO 00/042024, the amorphous rosuvastatin of the Formula (II) obtained according to the process of European Patent No. 521471 can be used in the pharmaceutical technology with great difficulties. In order to eliminate this disadvantage, crystalline forms having more advantageous physical properties than the amorphous product are prepared. The manufacture of crystalline rosuvastatin calcium salt, however, is a manufacturing process requiring high production volume and results in great loss of material.
The basic problem in the manufacture of the calcium salt of rosuvastatin resides in the fact that the primary product obtained is poorly filterable and can not be purified in an easy way. Published International Patent Application WO 04/14872 discloses non-crystalline product having advantageous filterability. According to the process of said application, the calcium salt of advantageous particle size is prepared by reacting an alkaline metal, ammonium, methylammonium or tris(hydroxymethyl)-methylammonium salt of rosuvastatin with calcium chloride in an aqeuous solution.
In the published International Patent Application No. WO 01/60804, there are disclosed high purity ammonium-, lithium- or magnesium salts of rosuvastatin of the Formula (II) in order to solve production problems which arose during the manufacture of amorphous rosuvastatin. Starting from the above-mentioned salts, it is possible to prepare amorphous rosuvastatin in a quality suitable for the manufacture of medicinal products.
Published International Patent Application WO 2005/051921 discloses a similar process, wherein isopropylammonium or cyclohexylammonium salts of rosuvastatin are produced in high purity and said salts are transformed into sodium salt or high purity amorphous calcium salt of rosuvastatin.
Published International Patent Application No. WO 2005/040132 discloses amorphous rosuvastatin calcium salt of high diastereomeric purity. According to the disclosed process, the primary product amorphous rosuvastatin calcium salt is crystallized in the first stage, the product thus obtained is subsequently transformed into the amorphous form.
In summary, it can be concluded that according to the state of the art, the manufacture of rosuvastatin calcium salt suitable for the preparation of medicinal products is a particularly intricate process. The crude product must be submitted to further purification and crystallization steps in order to obtain a suitable product with regard to purity and physical properties. The known processes are difficult to operate in an industrial scale process and the use of such known processes often results in a significant loss of material and is therefore uneconomical.